N-[(guanylmercapto)alkyl]-c-diaryl-methyl-piperidines



United States Patent N -[(GUANYLMERCAPTO)ALKYL]-C-DIARYL- IMETHYL-PIPERIDINES Robert Paul Mull, Flor-ham Park, and. Renat HerbertMizzoni, Long Valley, N.J., assignors to Ciba Corporation, New York,N.Y., a corporation of Delaware No Drawing. Continuation-impart ofapplication Ser. No. 416,144, Dec. 4, 1964. This application Aug. 16,1965, Ser. No. 480,136

18 Claims. (Cl. 260293.4)

ABSTRACT OF THE DISCLOSURE The invention is directed to compounds usefulas gastric secretion inhibitors and having the formula in which one ofthe radicals R R and R stands for a monocyclic carbocyclic aryl radicaland the other two stand for hydrogen, monocyclic cycle-lower alkyl oralkenyl and/ or monocyclic carbocyclic aryl, m stands for an integerfrom 1 to 4, n for an integer from '5 to 8, p for an integer from 2 to'8 and X for one of the groups 3,366,637 Patented Jan. 30, 1968 in whicheach of the radicals R, R' and R" represents hyin which each of theradicals R, R and R" stands for hydrogen, lower alkyl or alkenyl,monocyclic cycloalkyl or cycloalkenyl, monocyclic cycloalkyl-1ower alkylor -alkenyl, monocyclic carbocyclic aryl-lower alkyl or -alkenyl ormonocyclic carbocyclic aryl and acid addition salts thereof.

cyclic ring, quaternaries and salts of these compounds, I

as well as methods for their preparation.

The mercaptoalkyl group of these compounds attached to theimino-nitrogen, more especially is a mercaptolower alkyl group in whichthe mercapto group is separated from the imino-nitrogen by at least twocarbon atoms. Its alkyl chain may be straight or branched and preferablycontains 2 to 4 carbon atoms. Examples for the mercaptoalkyl group arethe following: l-mercaptoy -P Py p w y y (3), -butyl-(4), -heXyl-(6),-heptyl-(5), -octy1-(4) or 2- methyl-propyl-(Z); 2-mercapto-propyl-(3),-butyl-(3), -butyl-(4) or pentyl-(S); 3-mercapto-butyl-(4) or -hexyl-(6). The mercapto group thereof may be free or substituted; itpreferably stands for a member selected from drogen or a loweraliphatic, araliphatic or aromatic hydrocarbon radical, especially loweralkyl, such as methyl, ethyl, nor i-propyl, n-, i-, secondary-ortertiary-butyl, pentyl, hexyl or heptyl, lower alkenyl, such as allyl ormethallyl, cycloalkyl or cycloalkenyl containing preferably 5 to 6 ringcarbon atoms such as cyclopentyl, cyclohexyl, cyclopentenyl orcyclohevxenyl, cycloalkyl-lower alkyl or-alkenyl containing preferably 5to 6 ring carbon atoms, such as cyclopentylethyl, cyclohexylmethyl orcyclopentylallyl, aryl-lower alkyl or-alkenyl, especially monocycliccarbocyclic aryl-lower alkyl or-alkenyl, such as benzyl, phenethyl -(1)or -(2) or cinnamyl or monocyclic carbocyclic aryl. These hydrocarbonradicals may be unsubstituted or substituted, especially in the aromaticpart, by one or more than one of the same or of different substituents,such as lower alkyl, e.g. methyl ethyl, n-or i-propyl, free oretherified hydroxy or mercapto, e.g. methoxy, ethoxy or methylenedioxy,methylor ethyhnercapto, halogen, e.g. fiuoro, chloro or bromo,trifluoromethyl, nitro or amino, for example, lower alkylor di-loweralkylamino, e.g. methylamino, ethylamino, dimethylamino, diethylamino ormethylethylamino.

The alkyleneimino ring of the compounds of this invention, moreespecially contains a straight or branched alkylene group and havingfrom 3 to 8 ring carbon atoms. Above all, it represents piperidino, butalso pyrrolidino, 1,5-, 1,6- of 2,5 hexamethyleneimino, 1,5-, 1,6-, 1,7-or 2,6 heptamethyleneimino or 1,8-, 3,6- or 3,7-octa' methyleneimino.

The unsaturated hydrocarbon radical attached to any of the ring carbonatoms of the alkyleneimino ring available for substitution above all isan aralkyl, cycloalkylor cycloalkenylaralkyl or a partially hydrogenatedaryl radical. More especially it is a lower alkyl group containing oneto three monocyclic, carbocyclic aryl radicals, such as benzyl,diphenylmethyl (benzhydryl), triphenylmethyl, phenethyl-(l) or -(2),1,1- or 1,2- diphenylethyl, 1,1,1 triphenylethyl-(Z), phenylpropy1-( 1),-(2) or -(3), 1,1-, 2,2-, 3,3-, 1,2-, 1,3- or 2,3-diphenylpropyl-(S),1,3 diphenylpropyl (2), 1,2,3 triphenylp w p y y or 2,-2-, 1,3-, or2,3-diphenyl-butyl-(3) or -(4) or tribenzylmethyl; or a lower alkylgroup containing at least one cyclo-lower alkyl or alkenyl group,containing preferably 5 or 6 ring carbon atoms, and at least onemonocyclic carbocyclic aryl radical, but containing not more than 3cyclic radicals, such as u-cyclopentyL, u-cyclohexylor a-cyclohexen (2)yl-benzyl, uor fi-cyclohexyl-phenethyl-(2) or l-cyclopentylorl-cyclopenten-(2)-yl-2,2- diphenylethyl-(Z); or a partially hydrogenatedhior tricyclic carbocyclic aryl radical, such as indenyl-(l),hydrindenyl-(Z), tetralinyl-( 1) or -(2), fluorenyl-(9),acenaphthenyl-(l), 9,10 dihydro-anthrazenyl (9) or 1,2,3trihydrophenalenyl (2). These hydrocarbon radicals-maybe unsubstitutedor substituted, especially in the aromatic part, by one or more than oneof the same or ofdiiierent substituents, such as those mentioned for R.

The new compounds possess valuable pharmacological properties. Forexample, they cause -a marked decrease of the gastric secretion,especially of gastric hydrochloric acid, which can be demonstrated, forexample, at a dosage range between about 1-15 mg./kg./day, preferably5-10 mgL/kg/ day, on the dog, of which the gastric secretion is inducedeither by food or by parenteral application of histamine. The compoundsof this invention, are

therefore, useful in the management and treatment of gastric irritationor of gastric ulcers by reducing the anism of the gastric secretion.Furthermore, the new compounds are useful starting materials orintermediates in the manufacture of other valuable compounds, especiallymedicines.

Particularly useful are compounds of the general formula:

R1\ R2( m 2m2) in which each of the radicals R, R and R stands forhydrogen, lower alkyl or alkenyl, monocyclic cycloalkyl or cycloalkenyl,monocyclic cycloalkyl-lower alkyl oralkenyl, monocyclic carbocyclicaryl-lower alkyl or alkenyl or monocyclic carbocyclic aryl, and acidaddition salts thereof.

Compounds that are especially valuable are those of the formula:

in which each of the groups R; and R stands for phenyl, loweralkyl-phenyl, lower alkoxy-phenyl, halophenyl, trifluoromethylphenyl ordi-lower alkylamino-phenyl, each of the groups R and R stands forhydrogen or lower alkyl and q stands for an integer from 2 to 4, andacid addition salts thereof.

Above all, the present invention concerns compounds of the formula:

H RfH-C H2 NH: 0 111 N-C qH2q-SO CID-CH2 \NH in which R.,, R and q havethe meaning given above, and. acid addition salts thereof.

The new compounds are prepared by methods in themselves known. Forexample, the procedure is (a) To replace in an N-(R-alkyl)-alkyleneimine, containing in the ring an unsaturated hydrocarbonradical, the substituent R capable of being converted into mercapto, bya free or substituted mercapto group or (b) To add a compound,containing a free mercapto group, to an N-alkenyl-alkyleneiminecontaining in the ring an unsaturated hydrocarbon radical or (c) Toreact an N-unsubstituted alkyleneimine, containing in the ring anunsaturated hydrocarbon radical, with a reactive O-esterifiedmercapto-alkanol or (d) To reduce in an N-mercaptoalkyl-alkyleneiminecontaining in the ring an unsaturated hydrocarbon radical and in thering and/or alkyl chain at least one carbamyl or ethenylene grouping,said grouping to the 'methyleneimino or ethylene grouping respectively,and, if desired, converting the final products into each other,converting a resulting free compound into a salt or quaternary ammoniumcompound or converting a resulting salt into the free compound or intoanother salt.

The substituent R capable of being converted into mercapto represents,for example, esterified hydroxy, preferably halogeno, e.g. chloro,bromo, or iodo, or aliphatic or aromatic sulfonyloxy, such as methane-,ethane, benzeneor p-toluene-sulfo nyloxy. The N-(R -alkynalkyleneiminestarting compounds may be reacted with a compound containing a freemercapto group, such as hydrogen sulfide, a thio-alcohol or thiophenol,thiocyanic acid, a monoor dithiocarbamic acid, an ester thereof or athiourea containing at least one hydrogen atom, or advantageously ametal salt thereof, especially an alkali metal, e.g. sodium or potassiumsalt thereof.

A reactive O-esterified mercapto-alkanol is, for example, a halo-orsulfonyloxy-alkane containing preferably a substituted mercapto group,which is separated from the halogen, e.g. chloro or bromo atom or thesulfonyloxy, e.g. p-toluene sulfonyloxy group, by at least two carbonatoms.

In the N-mercaptoalkyl-al'kleneimine starting compounds in which acarbonyl group is connected with the imino nitrogen atom (i.e. forming acarbamyl group), the carbonyl group can be reduced, for example, with acomplex light metal hydride, e.g. lithium aluminum hydride. Saidstarting compounds that contain a double bond, (or ethenylene groupingrespectively) it preferably extends from the ring carbon atom thatcarries the unsaturated hydrocarbon radical, may be reduced withcatalytically activated hydrogen, e.g. hydrogen in the presence of apalladium catalyst.

The final products of this invention may be converted into each other bymethods in themselves known. Thus, for example, a compound obtainedcontaining the free mercapto group can be reacted with a reactivelyesterified lower aliphatic or araliphatic alcohol, e.g. a lower alkylhalogenide or sulfate, an aromatic diazonium compound, e.g. benzenediazonium chloride, a lower aliphatic or araliphatic hydrocarboncontaining an olefinic double bond, e.g. ethylene, cyclopentene orstyrene, a halocyan, e.g. bromocyan, an isocyanate or thioisocyanate, acarbamic or thiocarbamic acid halide or a cyanamide, in order to obtainthe hereinbefore described compounds containing a substituted mercaptogroup. Furthermore the amidino-mercaptanes (isothioureas) obtained maybe hydroyzed, for example, with aqueous alkali metal hydroxides in orderto obtain the unsubstituted mercaptanes, the cyano-mercaptanes(rhodanides) may be additively combined with water, hydrogen sulfide,alcohols or thiols, preferably under acidic conditions, e.g. in thepresence of hydrochloric acid, or carbamylor thiocarbamyl-mercaptanes(thioor dithiourethanes) with aliphatic or araliphatic halogenides. Thequaternaries are obtained from the free compounds by reacting thempreferably with reactively esterified lower alkanols.

The above mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingagents and/ or of inert atmospheres, at atmospheric or superatmosphericpressure, at low temperatures, room temperature or elevatedtemperatures. Condensing agents are preferably used in the reaction ofcompounds with a reactive esterified hydroxy group whereby an acid issplit off. They are especially inorganic or organic bases, for example,alkali metal carbonates, such as potassium carbonate, or tertiarynitrogen bases, such as trimethylamine or pyridine.

The end products are obtained in the free form or in the form of theirsalts, depending on the conditions under which the process is carriedout; the salts are also included in the present invention. Salts thatare obtained can be converted into the free bases in known manner, forexample, with alkalis or ion exchangers. Free bases that are obtainedcan be converted into salts by reaction with organic or inorganic acids,especially those that are suitable for the formation of therapeuticallyuseful salts. Such acids are, for example, hydrohalic acids, e.g.hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric orperchloric acid, aliphatic, alicyclic, araliphatic, aromatic orheterocyclic carboxylic or sulfonic acids, for example, formic, acetic,propionic, succinic, glycollic, lactic, malic, citric, ascorbic, maleic,hydroxymaleic, pyroracemic, phenylacetic, benzoic, aminobenzoic,anthranilic, hydroxybenzoic, salicylic, aminosalicylic, embonic,nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic,naphtalenesulfonic and sultanilic acid; methionine, tryptophan, lysineand arginine.

These and other salts of the new compounds, for example, the picrates,can also be used for purification of the bases obtained; the bases areconverted into salts, the salts are separated and the bases areliberated from the salts. In view of the close relationship between thefree compounds and the compounds in the form of their salts, Whenever afree base is referred to in this context, a corresponding salt is alsointended, provided such is possible or appropriate under thecircumstances.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components may be used in the form of their salts.

Mainly, those starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being especially valuable.

The starting materials are known, or if they are new, may be prepared bymethods in themselves known. Several of the new starting materials aredescribed in our copending applications Ser. No. 392,931, filed Aug. 28,1964, U.S. Patent No. 3,252,983, Ser. No. 416,154, filed Dec. 4, 1964(now abandoned) and Ser. No. 480,147 filed Aug. 16, 1965, now abandoned.

The N-mercaptoalkyl-alkyleneimino starting compounds, containing atleast one carbamyl or ethenylene group, may by prepared analogous to themethod described under (a) and (c) by selecting the appropriatereagents, for example, by reaction of an N-haloalkylalkenyleneimineor-oxoalkyleneimine containing in the ring an unsaturated hydrocarbonradical, with a compound containing a free mercapto group, eg. thosementioned above or by reaction of a corresponding N-unsubstitutedalkenyleneimine or oxoalkyleneimine with a haloalkylmercapto compound orby reaction of a corresponding N-unsubstituted alkyleneimine oralkenyleneimine with a mercapto-alkanoyl halide.

Starting materials or final products that are mixtures of isomers may beseparated into single isomers by methods in themselves known. Forexample, compounds that contain one or more asymmetrical carbon atomsmay be in the form of racemate mixtures, pure racemates or opticalantipodes.

Mixtures of racemates, by virtue of the physicochemical differencesbetween the components, can be resolved into the stereoisomeric pureracemates (diastereoisomers), for example, by chromatogprahy and/orfractional crystallization. Racemic products can likewise be resolvedinto the optical antipodes, for example, by reaction with opticallyactive acids, separation of the diastereomeric salts and liberation ofthe bases from the salts.

The new compounds can be used in the free form or in the form of theirsalts, for example, for the manufacture of pharmaceutical preparationscontaining the said compounds in admixture with organic or inorganic,solid or liquid pharmaceutical excipients suitable especially forenteral but also for parenteral administration. Suitable excipients aresubstances that do not react with the new compounds, for example, water,gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc,vegetable oils, benzyl alcohols, gums, propylene glycols, whitepetroleum jelly and other known medicinal excipients. The pharmaceuticalpreparations may be, for example, tablets, dragees tor capsules, or inliquid form as solutions, suspensions, or emulsions. They may besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure or buffers. They may further contain othertherapeutically valuable substances. The pharmaceutical preparations areprepared by conventional methods.

The following examples illustrate the invention, temperatures are givenin degrees centigrade and all parts given are parts by weight.

Example 1 The solution of 3.55 g. ofN-(2-chloro-ethyl)-3-benzhydryl-pipieridine hydrochloride in 50 m1. ofethanol is added with stirring to a solution of 0.86 g. of thiourea in25 ml. of ethanol and the mixture refluxed for 6 hours. Thereupon it isconcentrated under reduced pressure, the residue triturated with etherand the whole filtrated. The filter residue is recrystallized fromethanol-ether in order to obtain the pureN-(Z-guanylmercapto-ethyl)-3-benzhydryl-piperidine hydrochloride of theformula:

melting at 195-208.

Example 2 The suspension of 25.1 g. of 3-benzhydryl-piperidine, 11.0 g.of ,8-chloroethyl-methylsulfide, 15.0 g. of sodium carbonate in 250 ml.of butanol containing a trace of water, is refluxed with stirring for 24hours. After cooling the reaction mixture is filtered, the filtrateconcentrated under reduced pressure and the residue distilled in a highvacuum. There is obtained the N-(Z-methylmercapto-ethyl)-3-benzhydryl-piperidine of the formula:

Example 3 To the suspension of 3.9 g. ofN-(2-guanylmercaptoethyl)-3-benzhydryl-piperidine hydrochloride in 10*ml. of water the solution of 8.1 g. of sodium hydroxide in 30 ml. ofwater is added with stirring and stirring is continued for 5 hours atroom temperature. Thereupon the reaction mixture is saturated withsodium choride, extracted with diethyl ether and the extractconcentrated in vacuo in a stream of nitrogen. The residue representsthe N-(2- mercapto-ethyl)-3-benzhydryl-piperidine of the formula:

CaH5

Example 4 The boiling solution containing 25.0 g. of N-allyl-3-benzhydryl-piperidine and a trace of ben-zoyl peroxide in ml. of benzeneis treated with methyl mercaptan for 24 hours. After concentration ofthe reaction mixture under reduced pressure and distillation of theresidue in a Example Other compounds of this invention which areprepared according to the above described and illustrated procedure byselecting equivalent amounts of the appropriate starting materials are,for example, the following:

gradually adding 4,000 ml. of boiling purified Water. The mixed powdersare granulated with the above paste, using additional Water as required.

The resulting moist mass is passed through a mill, using a No. 4Ascreen, placed on trays and dried at 3 8 C. until the moisture contentis between 2 percent and 3 percent. The granules are broken on a mill,passed through a No. 16 screen, and treated with the stearic acid andthe calcium stearate, both screened through a No. 20 screen. Aftermixing for twenty minutes, the granulation is compressed into tablets,each weighing 0.25 g., using inch dies, standard concave punches, uppersbisected, lowers monogrammed.

Reagent Final Product Starting MaterialN-(2-chloro-ethyl)-2-benzhydryl-piperidine hydrochloride.N-(2-chloro-ethyl-4-benzhydryl-piperidine hydrochloride.N-(3-ehloro-propyl)-3-(di-paratolyl-methyD-prperrdine hydrochloride.N-(2-chloro-ethyD-3-(di-para chlorophenyl-methyl)- piperidine. vN-(2-chloroethyl)-3-(u-cyclohexyl-benzyD-prperrdine hydrochloride. I3-(di-para methoxy-phenyl-methyl)-p1per1d1ne Thiourea PotassiuJuthioeyanate N,N-diethyl-thiourea 'y-B romopropyl-b enzylsulfideN-(Z-guanylmercapto-ethyl)-2-benzhydryl-piperidine hydrochloride.

N-(Z-g-uanylmercaptoethyl)-4-benzhydryl-piperidine hydrochloride.

N-(3-guanylmercapto-propyl)-3-(di-paratolyl-rnethyD- piperidinehydrochloride.

N-(2-cyanomercapto-etliyl) 3 (di-para chlorophenylmethyD- iperidine.

N-[2-(N,N -diethyl guanylmercapto)-ethyl]'3-(acyclohexyl-b enzyl)-piperidine hydrochloride.

N -(3-benzylrnereaptopropyl)-3-(di-paramethoxyphenyl-methyl)-piperidine.

3.flu 1e1 y1-(9)-piperidine B-chlorpethyl-phenylsulfideN-(2-phenylmercapto-ethyl)-3-flu0Ienyl-(9)- iperldine. 1 13-(a-para-fiuoro-phenyl-benZyD- N,N-d1methyltlnoureaN-[2(N,N-din1ethylguanylmercanto -ethy -3(apiperidine hydrochloride.para fluorophenyl-benzyl)-piperidine hydrochloride.N.(2-qh1oro-ethy1)-3-benzhydryl-p1perldm8 ThiourethaneS-[2-(3-benzhydryl- 'peridino)-ethyl]-tl1iourethane3-(1,2-diphenyl-ethyl)-piperidine 3-(di-ortl1o methoxyphenyl-methyl)-piperidine N-(3-bromo-propyl)-3-(di-paradiethylarninophenyl-rnethyl)-pip eridine.N-(Z-bromoethyl)-3-triphenyl-rnethyl-pip eridmefl-chloroethyl-eyelohexylsultlde ,5-chloropropyl-ethylsulfidehydrochloride.

N-(Q-cyclohexylmercapto-ethyl)-3-(1,2-diphenylethyl)-piperidine.

N-(3-ethylmereapto-propyl-Z)-3-(di-ortho methoxyphenyl-methyl)-piperidine.

N- (B-guanylrn ercapto-propyl) -3-(di-p aradl-ethylaminophenyl-methyl)-piperidine hydrobromide.

N(iZ-guauylniereapto-ethyl)3-triphenyl-methyl- I piperidinehydrobromide. 3.benzyl-p1pend1ne 3-br0m0 -m hyl-propyl-cyclo-N-(3-cyclopentylrnethyl-mercapto-2-metl1yl-pr0py1)- pentylmethyl-sulhde.3-benzyl-piperidine. N-(2- ;hl m-ethyl)-3-benzhydryl-pyrlolldme ThioureaN-(Z-guanylmercapto-ethyD-lH)eu hyd yl-pyrro din hydrochloride.hydrochloride. N-m thaHyLS-benzhydr'yl-plpelldlne Methyl mer apt nN-(a-meghylmereapto-2-methyl-propyl)-3-benzhydrylpiperi me. (3. t11i-buten-(2)-yl)-3-benzhydryl-pipendm do N-(2-methylmercapto-B-methyl-butyl) -3-benzhydry1- piperidine.

Example 6 Example 8 Preparation of 500 capsules each containing 0.01 g.of the active ingredient.

Ingredients: G.

N-(Z-guanylmercapto-ethyl)-3-benzhydrylpiperidine hydrochloride 5.000Lactose 85.000

PROCEDURE The ingredients are blended in a suitable mixer, sievedthrough a No. 40 screen and again mixed; portions weighing 0.18 g. eachof the resulting mixture are filled into No. 4 capsules.

Example 7 Preparation of 160,000 tablets each containing 0.025 g.

of the active ingredient.

Purified water, q.s.

PROCEDURE The hydrochloride, the lactose, 2,500 g. of the corn starch,the confectioners sugar and the colloidal silica are passed through aNo. 16 screen into a mixer and blended at low speed for twenty minutes.The remainder of the corn starch is suspended in a cold solution of thecolor in 1,000 ml. of purified water, and a paste is formed by Themixture of 10.0 g. 3-benZhydryl-piperidine, 8.62 g.Z-phenylmercapto-ethyi bromide, 15.0 g. sodium carbonate, 1 drop Waterand ml. benzene is refluxed for 6 hours while stirring. Hereupon it isfiltered, the filtrate concentrated and the crystals, separating onstanding in the cold are filtered off. The so-obtainedN-(2-phenylmercapto-ethyl)-3-benzhydryl-piperidine of the formula isrecrystallized from ethanol and melts at 99-100.

Example 9 To the solution of 3.5 g.N-(2-chloroethyl)-3-benzhydryl-piperidine hydrochloride in 50 ml.absolute ethanol, the solution of 1.14 g. N,N-dimethyl-thiourea in 30ml. absolute ethanol is added and the whole refluxed for 6 hours whilestirring, and stirring is continued overnight at room temperature. Thereaction mixture is concentrated in vacuo and the residue recrystallizedfrom ethanoldiethyl ether to yield theN-[2-(N,N-dimethyl-guanylmercapto) -ethyl]-3-benzhydry1-piperidinedihydrochloride of the formula C 11 NH orp N-CHaCH:-S-C

Cam N (CH3) 1.212101 which melts after drying in a high vacuum at149153.

'The' analogously prepared N-[2-(N,N-diethyl-guanylmercapto) -ethyl]-3-benzhydryl-piperidine dihydrochloride melts at 58-59" (at 119 clearmelt).

Example melting at 8690.

Example 11 To the solution of 1.32 g. N,N'-diethy1-thiourea in 35 ml.absolute ethanol, the solution of 3.5 g.N-(2-chloroethyl)-3-benzhydryl-piperidine hydrochloride in 50 ml.absolute ethanol is added while stirring and the mixture is refluxed for6 hours and stirred overnight at room temperature. Hereupon, it isevaporated under reduced pressure; the residue triturated with diethylether; the ether decanted off and the residue dried in a high vacuum.There is obtained the hygroscopic N-[2-(N,N-diethylguanylmercapto-ethyl] -3-benzhydryl-piperidine dihydrochloride of the formula In theanalogous manner, the N-[2-(N,N-diallylguanylmercapto) -ethyl]-3-benzhydrylpiperidine dihydrochloride is prepared from the equivalentamounts of starting materials; it melts at 65 and has the following.formula Example 12 The stirred mixture of 3.5 g. N-(2-chloroethyl)-3-benzhydryl-piperidine hydrochloride, 1.52 g. N-phenylthiourea and 100ml. anhydrous ethanol is refluxed for 6 hours and stirred overnight atroom temperature. The mixture is evaporated in vacuo and the residuetriturated with diethyl ether to yield theN-[Z-(N-phenyl-guanylmercapto) -ethyl] -3-benzhydryl-piperidinedihydrochloride of the formula melting at 90-100".

. 10 Example 13 The stirred mixture of 2.82 g. N,N'-dibenzyl-thiourea,3.5 g. N-(2-chloroethy1)-3-benzhydryl-piperidine hydrochloride and 275ml. anhydrous ethanol is refluxed for 6 hours, and stirring is continuedat room temperature overnight. It is evaporated in vacuo and the residuerecrystallized from anhydrous ethanolto yield the N-[2-(N,N'-dibenzylguanylmercapto) ethyl] 3 benzhydrylpiperidine dihydrochloride of theformula melting at 150-155".

Example 14 The stirred mixture of 4.0 g.N-(Z-chloroethyl)-3-(dip-tolyl-methyD-piperidine, 0.865 g. thiourea and80 ml. anhydrous ethanol is refluxed and stirred for 8 hours and leftstirring overnight at room temperature. It is evaporated in vacuo, theresidue recrystallized from ethanoldiethyl ether and dried in a highvacuum to yield the hygroscopicN-(Z-guanylmercapto-ethyl)-3-(di-p-tolyl-methy1)-piperidinedihydrochloride of the formula By replacing in the above example thethiourea by 1.37 g. N-allyl-thiourea, the N-[2-(N-allyl-guanylmercapto)-ethyl]-3- (di-p-tolyl-methyl)piperidine dihydrochloride to the formulais obtained.

Example 15 The mixture of 3.5 g. N-(2chloroethyl)-2-(2,2-diphneyl-ethyl)-piperidine hydrochloride, 2.94 g.N,N-dimethyl-thiourea and ml. absolute ethanol is refluxed for 6 hourswhile stirring. It is evaporated in vacuo and the residue trituratedwith diethyl ether to yield the N- [2-(N,N dimethyl guanylmercapto)ethyl] -2-(2,2-dipheny1-ethyl)-piperidine dihydrochloride of the formulamelting at 60.

- Example 16 The stirred mixture of 4.0 g.N-(2-chloroethyD-4-benzhydryl-piperid-ine hydrochloride, 0.95 g.thiourea and 80 ml. absolute ethanol is refluxed for 8 hours and stirredovernight at room temperature. It is evaporated under reduced pressure,the residue triturated with diethyl ether and the hygroscopic crystalsdried in a high vacuum, to yield theN-(Z-guanylmercapto-ethyl)-4-benzhydry1-piperidine dihydr-ochloride ofthe formula 11 Example 17 The mixture of 4.0 g.N-(2-chloroethyl-4-benzhydrylpiperidine hydrochloride, 1.47 g.N-allyl-thiourea and 80 ml. anhydrous ethanol is refluxed for 6 hourswhile stirring and kept at room temperature overnight. It is evaporatedin vacuo, the residue tritrated with petroleum ether and the crystalsformed are filtered 01f, representing the N [2 (Nallyl-guanylmercapto)-ethyl]-4-benzhydrylpiperidine dihydrochloridemonohydrate of the formula which is very hygroscopic.

In the analogous manner, the N-[2(N-methyl-N- phenyl guanylmercapto)ethyl]-4-benzhydryl-piperidine dihydrochloride of the formula isprepared by substituting the N-allyl-thiourea by 2.07 g.N-methyl-N-phenyl-thiourea.

Example 18 The mixture of 4.0 g.2-(2-chloroethyl)-3-(di-p-tolylmethyl)-piperidine hydrochloride, 1.52 g.N-ethyl-thiorea and 80 ml. anhydrous ethanol is refluxed for 8 hourswhile stirring and kept overnight at room temperature. It is evaporatedin vacuo, the residue recrystallized from ethanol-diethyl ether anddried in a high vacuum to yield the hygroscopicN-[2-(N-ethyl-guanylmercapto)-ethyl]-3- (di-p-tolyLmethyl)-piperidinedihydrochloride of the formula The compounds of the present invention,mentioned in this and in previous examples, without melting or boilingpoint, are either too hygroscopic for estimating the MP. or notdistillable; they do, however, analyze correctly.

What is claimed is:

1. A member selected from the group consisting of compounds having theformula:

in which one of the radicals R R and R stands for a R phenyl radical andthe other two stand for a member selected from the group consisting ofhydrogen, monocyclic cyclo-lower alkyl, monocyclic cyclo-lower alkenyland R.,phenyl, and R stands for a member selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, halogeno,trifluoromethyl and di-lower alkylamino, m stands for an integer from 1to 4, n for an integer from 5 to 8, p for an integer from 2 to 8 andeach of the radicals R, R and R" stands for a member selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, monocycliccyclo-lower alkyl, monocyclic cyclo-lower alkenyl, monocycliccyclo-lower alkyl-lower alkyl, monocyclic cyclo-lower alkyl-loweralkenyl, R -phenyl-lower alkyl, R -phenyl-lower alkenyl and monocycliccarbocyclic aryl and acid addition salts thereof.

12 2. A member selected from the group consisting of compounds havingthe formula:

in which each of the groups -R.,, and R stands for a member selectedfrom the group consisting of phenyl, lower alkyl-phenyl, loweralkoxy-phenyl, halophenyl, trifluoromethyl-phenyl and di-loweralkylamino-phenyl, each of the groups R and R stands for a memberselected from the group consisting of hydrogen and lower alkyl and qstands for an integer from 2 to 4 and therapeutically acceptable acidaddition salts thereof.

3. A member selected from the group consisting of compounds having theformula:

in which each of the groups R and R stands for a member selected fromthe group consisting of phenyl, lower alkyl-phenyl, lower alkoxy-phenyl,halophenyl, trifluoromethyl-phenyl and di-lower alkylamino-phenyl and qstands for an integer from 2 to 4 and therapeutically acceptable acidaddition salts thereof.

4. N (2 guanylmercapto ethyl) 3' piperidine.

5. N [2 (N,N dimethyl guanylmercapto)-ethyl]- S-benzhydryl-piperidine.

6. N [2 (N,N diethylguanylmercapto) ethy11-3- benzhydryl-piperidine.

7. N [2 (N ethyl guanylmercapto) ethyl] 3- benzhydryl-piperidine.

8. N [2:(N,N' diethyl-guanylmercapto) ethyl] 3- benzhydryl-piperidine.

9. N [2 (N,N diallyl guanylmercapto) ethyl]- 3-benZhydryl-piperidine.

10. N [2 (N phenyl guanylmercapto) benzhydryl-piperidine.

11. N [2 (N,N dibenzyl guanylmercapto) ethyl]-3-benzhydryl-piperidine.

12. N (2 guanylmercapto ethyl) 3 (di-p-tolylmethyl) -piperidine.

13. N [2 (N allyl guanylmercapto) (di-p-tolyl-methyl) pip eridine.

14. N [2 (N,N dimethyl guanylmercapto)- et-hyl] -2- (2,2-diphenyl-ethyl)-piperidine.

15. N (2 guanylmercapto ethyl) 4 benzhydrylpiperidine.

16. N [2 (N allyl guanylmercapto) benzhydryl-piperidine.

17. N [2 (N methyl N phenylguanylmercaptoethyl]-4-benzhydryl-piperidine.

18. N [2 (N ethyl guanylmercapto) ethyl-3-(dip-tolyI-methyl)-piperidine.

benzhydrylethyl1-3- ethyl] 3- ethyl] 4- NORMA S. MILESTONE, ActingPrimary Examiner. A. D. SPEVAQK, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,366,637 January 30 1968 Robert Paul Mull et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 12, lines 19 to 25, the formula should appear as shown below:

/CH 5 7 I CH CH NH CH N C H S C CH CH NH same column 12 line 40 "N- [2(N,N should read N [2- (N,N

Signed and sealed this 3rd day of February 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents

